A number of light-mediated therapies, such as photodynamic therapy (PDT), photoactivation and photochemical internalization have been, and are continuing to be, developed for treating cancer. Photodynamic therapy is used, or is under investigation, for a range of human tumors, but despite its well- documented strengths suffers a number of critical limitations: 1) The tumor has to be accessible to an external light source. 2) Achieving uniform and known dosimetry due to the uneven and rapid attenuation of light in tissue is a significant problem. 3) Photosensitizers are limited to those with reasonable absorption beyond 600 nm due to light penetration challenges. 4) Only detected tumors can be treated - ineffective against metastatic disease. Recently, the fact that many medical radionuclides emit optical photons via the Cerenkov effect has been exploited for imaging purposes. This emitted light is heavily weighted towards the ultraviolet and blue part of the spectrum. Furthermore, in nuclear medicine there are a wide range of tumor-targeted radiopharmaceuticals used both for diagnosis and at higher activity levels for therapy, that have good tumor specificity. This opens up the very interesting possibility of using the Cerenkov light generated from targeted radiopharmaceuticals as an internal light source to activate phototherapies such as PDT. If possible, this would circumvent many of the limitations of light delivery for PDT described above, as light would be emitted within the tumor cells, and the systemic injection of the radiopharmaceutical could potentially lead to PDT in both primary tumors and metastatic disease. There also may be synergistic effects of simultaneous PDT and radionuclide therapy. This exploratory R21 proposal will use in vitro and in vivo experiments to assess the feasibility of Cerenkov-activated PDT under well-controlled conditions and provide data that is necessary to determine if there is value in then pursuing this attractive concept in clinically-relevant preclinical trials in animals.